rhizoxin and Carcinoma--Non-Small-Cell-Lung

In a multicentre trial of the EORTC-Early Clinical Trials Group (ECTG) we treated 31 chemotherapy-naive patients with advanced non-small-cell lung cancer (NSCLC) with rhizoxin, a novel tubulin-binding agent. The drug was given as an i.v. bolus injection at 2 mg m-2 once every 3 weeks in an outpatient setting. Prophylactic antiemetics were not routinely given. Of the 29 eligible patients, nine had been treated surgically and three had received radiotherapy. The main toxic effects observed were stomatitis (34% of cycles) and neutropenia (41% of cycles). Neutropenic fever was rare (3% of cycles). Twenty-seven patients were evaluable for response. There were four partial responses (15%), while 13 patients (48%) showed stabilisation of their disease. The median duration of response was 7 months (range 6.0-10.7 months) and median survival from the start of rhizoxin treatment was 6 months (range 2-14.7 months). Rhizoxin as single agent shows activity in patients with advanced NSCLC.

Topics: Adult; Aged; Antibiotics, Antineoplastic; Carcinoma, Non-Small-Cell Lung; Female; Hematopoiesis; Humans; Lactones; Lung Neoplasms; Macrolides; Male; Middle Aged

Rhizoxin is a macrocyclic lactone compound that binds to tubulin and inhibits microtubule assembly. Rhizoxin demonstrated preclinical anti-tumour activity against a variety of human tumour cell lines and xenograft models. Phase I evaluation found a maximum tolerated rhizoxin dose of 2.6 mg m-2, with reversible, but dose-limiting, mucositis, leucopenia and diarrhoea. Clinical trials were then initiated by the EORTC ECSG in melanoma, breast, head and neck, and non-small-cell lung cancers with the recommended phase II rhizoxin dose of 2 mg m-2. Pharmacological studies were instituted with the phase II trials to complement the limited pharmacokinetic data available from the phase I trial. Blood samples were obtained from 69 of 103 eligible patients enrolled in phase II rhizoxin studies, and these were evaluable for pharmacokinetic analysis in 36 patients. Plasma rhizoxin concentrations were determined by high-performance liquid chromatography (HPLC), and post-distribution pharmacokinetic parameters were estimated by a one-compartment model. Rhizoxin was rapidly eliminated from plasma, with a median systemic clearance of 8.41 min-1 m-2 and an elimination half-life of 10.4 min. Rhizoxin area under the concentration-time curve (AUC) was higher in patients obtaining a partial response or stable disease than in those with progressive disease (median 314 vs 222 ng ml-1 min; P = 0.03). As predicted from previous studies, haematological and gastrointestinal toxicity was observed, but could not be shown to be related to rhizoxin AUC. This study demonstrated the rapid and variable elimination of rhizoxin from the systemic circulation. The presence of pharmacodynamic relationships and the low level of systemic toxicity suggest that future trials of rhizoxin with alternative dosage or treatment schedules are warranted.

Topics: Antibiotics, Antineoplastic; Area Under Curve; Breast Neoplasms; Carcinoma, Non-Small-Cell Lung; Female; Head and Neck Neoplasms; Humans; Injections, Intravenous; Lactones; Lung Neoplasms; Macrolides; Male; Melanoma; Treatment Outcome

Rhizoxin is a new macrocyclic lactone isolated from the fungus Rhizopus chinensis. In an attempt to predict the effectiveness of rhizoxin in the treatment of lung cancer, we compared the antitumor activity of rhizoxin with those of cisplatin and etoposide using four small cell lung cancer (SCLC) cell lines, SBC-2, -3, -4, and -7, and two non-small cell lung cancer (NSCLC) cell lines, ABC-1 and EBC-1. The concentrations producing 50% inhibition of the growth of these cell lines (IC50) for each drug were obtained by MTT assay. The IC50 of rhizoxin for these cell lines ranged 0.408 nM to 1.56 nM, which were significant lower than those of cisplatin (660 nM to 16,300 nM) and etoposide (275 nM to 31,300 nM). The ratio of IC50 for the most sensitive cell line, SBC-3, to that for the most resistant cell line was less than 4-fold in rhizoxin, in contrast to more than 20-fold in cisplatin and 100-fold in etoposide. Cross-resistance of rhizoxin to cisplatin and etoposide was investigated using a cisplatin-resistant SCLC subline, SBC-3/CDDP, and an etoposide-resistant SCLC subline, SBC-3/ETP. Of interest, the parent cell line, and the resistant sublines were equally sensitive to rhizoxin, indicating rhizoxin being non-cross-resistant to cisplatin and etoposide. In conclusion, rhizoxin may be beneficial in the salvage chemotherapy of drug-resistant SCLC and non-SCLC.

Topics: Antibiotics, Antineoplastic; Carcinoma, Non-Small-Cell Lung; Carcinoma, Small Cell; Cisplatin; Drug Resistance; Drug Screening Assays, Antitumor; Etoposide; Humans; Lactones; Lung Neoplasms; Macrolides; Tumor Cells, Cultured